Expression of alpha-secretion mutant APP/RK in mouse brain results in a progressive disorganization of the central nervous system, exemplified by behavioral deficits, premature death and neuropathology. Here we report on the progressive nature of this CNS disorder as indicated by the age dependency of the neophobic reaction in the open-field test. The earlier reported NMDA hypo-sensitivity in the transgenic APP/RK mice is likely to represent a subtle functional disturbance, since no changes in NMDA receptor density or distribution could be detected. None of the typical neuropathological hallmarks of Alzheimer's Disease, i.e. amyloid deposits and neurofibrillary tangles are detected in the brain of these transgenic mice. Nevertheless, the progressive CNS disorder elicited in the transgenic APP/RK mice recapitulates certain features and symptoms of patients with Alzheimer's disease as discussed.